Trauma is the leading cause of death In this country in people under the age of 44 years. After major head injury, hemorrhage and its consequences are the most important causes of morbidity and mortality in these young, otherwise healthy individuals. This Center Grant proposal seeks to advance our understanding of the molecular mechanisms leading to organ injury and dysfunction in the severest forms of the hemorrhagic insult. By studying the rapid onset of organ injury, which is characteristic of severe hemorrhagic shock, the P.I. will exclude other delayed causes of morbidity such as sepsis due to infection, commonly encountered in trauma victims but also other critically ill patients. Stated another way, the P.I. believes the pathophysiology of the tissue injury and organ failure associated with hemorrhagic shock alone is a poorly understood and complex process that warrants focused and detailed study. Furthermore, a better understanding of this disease process will lead to more effective treatment strategies. The P.I. proposes that one of the keys to understanding organ injury resulting from hemorrhagic shock is to characterize the molecular events leading to the initiation and promotion of inflammatory changes in hemorrhagic shock. Most previous studies have examined the net effect of shock plus resuscitation on parameters of inflammation and organ damage. In contrast to these previous approaches, the P.I. divides the molecular events of the hemorrhagic shock into three distinct phases: the shock phase, the resuscitation phase, and the post-resuscitation phase. The P.I. hypothesizes that there are specific changes in gene expression in each phase that are induced by the effects of shock alone or the consequences of resuscitation following shock. These induced changes in gene expression promote inflammation and organ injury. The P.I. postulates that the duration and severity of the shock phase determine the degree of phenotypic changes and hence the intensity of the inflammatory response following resuscitation. The P.I. also proposes that the susceptibility of the host to subsequent inflammatory insults is enhanced by changes in gene expression resulting from the shock and resuscitation phases, and that this enhanced vulnerability prevents the resolution of the inflammatory response.